Zn2+ efflux through lysosomal exocytosis prevents Zn2+-induced toxicity

Zn2+ is an essential micronutrient and an important ionic signal whose excess, as well as scarcity, is detrimental to cells. Free cytoplasmic Zn2+ is controlled by a network of Zn2+ transporters and chelating proteins. Recently, lysosomes became the focus of studies in Zn2+ transport, as they were shown to play a role in Zn2+-induced toxicity by serving as Zn2+ sinks that absorb Zn2+ from the cytoplasm. Here, we investigated the impact of the lysosomal Zn2+ sink on the net cellular Zn2+ distribution and its role in cell death. We found that lysosomes played a cytoprotective role during exposure to extracellular Zn2+. Such a role required lysosomal acidification and exocytosis. Specifically, we found that the inhibition of lysosomal acidification using Bafilomycin A1 (Baf) led to a redistribution of Zn2+ pools and increased apoptosis. Additionally, the inhibition of lysosomal exocytosis through knockdown (KD) of the lysosomal SNARE proteins VAMP7 and synaptotagmin VII (SYT7) suppressed Zn2+ secretion and VAMP7 KD cells had increased apoptosis. These data show that lysosomes play a central role in Zn2+ handling, suggesting that there is a new Zn2+ detoxification pathway.